Histone lactylation is a novel type of post-translational modification,where a lactate molecule covalently binds to the lysine residues of histones.This modification plays a key role in cellular metabolic reprogramming,particularly in digestive system tumorigenesis and progression.In recent years,the role of histone lactylation in various malignancies has been increasingly recognized,highlighting its broad impact on tumor biology and clinical potential.This article focused on the research progress of histone lactylation in digestive system cancers,specifically analyzing its mechanisms in major gastrointestinal cancers such as gastric cancer,liver cancer,and colon cancer.Studies have shown that lactylation modifies histone lysine residues directly,regulating tumor cell gene expression and chromatin conformation,thereby promoting tumor proliferation,invasion,and metastasis.Lactylation affects histone-DNA interactions,altering chromatin openness and enhancing the transcriptional activity of oncogenes.In addition,targeted therapies that modulate lactation levels or inhibit lactation-related enzymes,such as lactate dehydrogenase inhibitors,lactate production inhibitors,and specific histone lactonases,are effective in inhibiting tumorigenesis and progression and have demonstrated potential therapeutic efficacy in preclinical models.This article systematically summarized the mechanisms of histone lactylation in various types of gastrointestinal cancers,offering new research directions and theoretical support for targeted therapeutic strategies based on lactylation modification.

Histone lactylation is a novel type of post-translational modification,where a lactate molecule covalently binds to the lysine residues of histones.This modification plays a key role in cellular metabolic reprogramming,particularly in digestive system tumorigenesis and progression.In recent years,the role of histone lactylation in various malignancies has been increasingly recognized,highlighting its broad impact on tumor biology and clinical potential.This article focused on the research progress of histone lactylation in digestive system cancers,specifically analyzing its mechanisms in major gastrointestinal cancers such as gastric cancer,liver cancer,and colon cancer.Studies have shown that lactylation modifies histone lysine residues directly,regulating tumor cell gene expression and chromatin conformation,thereby promoting tumor proliferation,invasion,and metastasis.Lactylation affects histone-DNA interactions,altering chromatin openness and enhancing the transcriptional activity of oncogenes.In addition,targeted therapies that modulate lactation levels or inhibit lactation-related enzymes,such as lactate dehydrogenase inhibitors,lactate production inhibitors,and specific histone lactonases,are effective in inhibiting tumorigenesis and progression and have demonstrated potential therapeutic efficacy in preclinical models.This article systematically summarized the mechanisms of histone lactylation in various types of gastrointestinal cancers,offering new research directions and theoretical support for targeted therapeutic strategies based on lactylation modification.

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Micronutrients (MNs), including vitamins and trace elements, play an indispensable role in human metabolism, immune function and other aspects. Due to the chronic microinflammation and long-term chemoradiotherapy, patients with malignant tumors often suffer from malnutrition, resulting in different degrees of MNs deficiency. In severe cases, MNs deficiency is closely related to the adverse clinical outcomes. Therefore, reasonable MNs supplementation is of great significance in improving the prognosis and quality of life of patients with tumors. Recently, multiple guidelines have made recommendations on the application of MN supplementation in various clinical settings, providing evidence for the standardized MN supplementation in patients with malignant tumors.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

Objective:To explore the clinical effects of combined medial and lateral approaches in treating of calcaneal fractures combined with sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus joint.Methods:Four adult cadaver specimens (8 feet) were selected, of which two (4 feet) were dissected on the medial side of the calcaneus to observe the adjacency and exposure range of sustentaculum tali. The other two specimens were simulated as medial and lateral approaches to reduce and fix calcaneal fractures. Retrospective analysis of 9 cases (9 feet) of Sanders II-IV type calcaneal fractures with combined medial and lateral approaches in the treatment of fractures and/or dislocations of sustentaculum tali-talus joint was performed. The average age was 49.9±11.3 (25-58) years. During the operation, the medial incision was made first, and the sustentaculum tali fracture was temporarily reduced and fixed to the talus. Then the lateral incision was made to expose the lateral side of the calcaneus, and the fracture fragments were reduced and fixed; the sustentaculum tali was fixed laterally with screws, and 2 cases were additionally fixed medially with absorbable rods. At the same time, six cases (8 feet) of calcaneal fractures with sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus were treated with lateral approach as a control group. The lateral sides of both groups were fixed with calcaneal locking plate and implanted with demineralized bone matrix into the cavity after articular surface reduction. The B?hler and Gissane angles of the two groups of patients were measured at 1 year after operation. The American Orthopaedic Foot and Ankle Society (AOFAS) scoring system was used to evaluate the clinical efficacy.Results:The sustentaculum tali-talus joint had a shape of an inverted "V" with two divided parts. The tip of the sustentaculum tali was exposed through the front window of the posterior tibial tendon. The sustentaculum tali and the medial side of the calcaneal body was completely exposed and fixed through the window between the posterior tibial tendon and the flexor digitorum longus tendon. The postoperative incision blood loss in the combined medial and lateral approach group was 73.6±4.3 ml, which was greater than that in the lateral approach group (70.6±7.1 ml) ( t=2.18, P=0.045). The lateral incision healed in both groups. The medial incision healed delayed in 1 patient in the combined medial and lateral approach group. The fractures in the combined medial-lateral approach group and the lateral approach group were both healed. The healing duration was 12.2±2.1 weeks and 12.8±2.8 weeks, respectively, without significant difference ( t=0.50, P=0.622). The B?hler angles of the combined medial-lateral approach group and the lateral approach group were 37.0°±5.7° and 27.9°±4.0° at 1 year after operation, respectively. These values were greater than the preoperative values of 4.7°±3.4° and 3.9°±2.9° ( P<0.05), with significant difference between groups ( t=3.76, P=0.002). The Gissane angles were 133.2°±9.8° and 139.1°±9.4° respectively, which were lower than those of 172°±7.3° and 175.6°±5.6° before operation ( P<0.05). There was no significant difference between the groups ( t=1.26, P=0.226). The AOFAS score of the combined medial and lateral approach group was 93.6±4.0 points, which was higher than that of the lateral approach group (84.3±8.2 points) ( t=3.03, P=0.008). Conclusion:Intra-articular calcaneal fractures combined with a high probability of sustentaculum tali fractures and/or dislocations of sustentaculum tali-talus joint. Compared with the simple lateral approach, the use of the combined medial-lateral approach and the medial-lateral surgical sequence is beneficial to restore the calcaneal alignment and anatomic shape, especially the alignment relationship of the medial calcaneus and talus, so as to obstain better early clinical outcomes.

Objective:To analyze and summarize the experience and shortcomings of this case in the process of abortion diagnosis and treatment of early pregnancy patients with hysteromyoma.Methods:A case of early pregnancy complicated with huge hysteromyoma was reported. The patient was planned to perform assisted uterine curettage after drug flow.Results:On the second day after taking mifepristone, the patient suddenly suffered from severe lower abdominal pain and less to moderate amount of ascites in the abdominal cavity. "Blood abdomen to be investigated: ectopic pregnancy? Spleen rupture? Hemorrhagic shock". The shock was corrected and exploratory laparotomy was performed at the same time. Repeated exploration of the pelvis and abdomen revealed no obvious bleeding point. During the operation, a small amount of blood was found in the vagina, and the villi were discharged automatically, so the uterus was cleared. The final consideration was that the bleeding was caused by the backflow of intrauterine bleeding to the abdominal cavity.Conclusion:Early pregnancy with hysteromyoma belongs to the category of high-risk abortion, especially hysteromyoma larger than 5 cm. Such patients need to strictly grasp the indications of drug abortion, and strengthen monitoring and management to avoid serious complications such as hemorrhagic shock.

Objective:To analyze and summarize the experience and shortcomings of this case in the process of abortion diagnosis and treatment of early pregnancy patients with hysteromyoma.Methods:A case of early pregnancy complicated with huge hysteromyoma was reported. The patient was planned to perform assisted uterine curettage after drug flow.Results:On the second day after taking mifepristone, the patient suddenly suffered from severe lower abdominal pain and less to moderate amount of ascites in the abdominal cavity. "Blood abdomen to be investigated: ectopic pregnancy? Spleen rupture? Hemorrhagic shock". The shock was corrected and exploratory laparotomy was performed at the same time. Repeated exploration of the pelvis and abdomen revealed no obvious bleeding point. During the operation, a small amount of blood was found in the vagina, and the villi were discharged automatically, so the uterus was cleared. The final consideration was that the bleeding was caused by the backflow of intrauterine bleeding to the abdominal cavity.Conclusion:Early pregnancy with hysteromyoma belongs to the category of high-risk abortion, especially hysteromyoma larger than 5 cm. Such patients need to strictly grasp the indications of drug abortion, and strengthen monitoring and management to avoid serious complications such as hemorrhagic shock.

Purpose: Cervical cancer is one of the most fatal diseases among women in under-developed countries. To improve cervical cancertreatment, discovery of new targets is needed. In this study, we investigated the expression of NUP210, miR-22, and Fas in cervicalcancer tissues and their functions in cell cycle regulation. Materials and Methods: We detected and compared the expression levels of NUP210, miR-22, and Fas in cervical cancer tissueswith paired normal tissues using immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction.NUP210 was knocked down in HeLa cells via lentivirus, followed by cell cycle and proliferation analysis. Using a luciferase reporterassay, we explored the link between miR-22 and NUP210. We overexpressed miR-22 in HeLa cells and analyzed cell cycle and proliferationfunction. We then overexpressed miR-22 in NUP210 knockdown cells to explore the connection between Fas and miR-22-NUP210 signaling. Results: We found that NUP210 was overexpressed in cervical cancer patients. Knocking down NUP210 restored cell apoptosisand proliferation. We confirmed miR-22 as a regulator of NUP210 and verified that miR-22 was inhibited in cervical cancer development.We also found that restoring miR-22 expression could induce cell apoptosis. Finally, we found that miR-22-regulated expressionof NUP210 could alter Fas expression and, in turn, elicit cell cycle arrest and proliferation. Conclusion miR-22 in cervical cancer is downregulated, resulting in NUP210 overexpression and inhibition of Fas-induced cellapoptosis.